RESUMO
Histone deacetylase 6 (HDAC6) is increasingly recognized for its potential in targeted disease therapy. This study delves into the mechanistic and structural nuances of HDAC6 inhibition by difluoromethyl-1,3,4-oxadiazole (DFMO) derivatives, a class of non-hydroxamic inhibitors with remarkable selectivity and potency. Employing a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) kinetic experiments, comprehensive enzymatic characterizations, and X-ray crystallography, we dissect the intricate details of the DFMO-HDAC6 interaction dynamics. More specifically, we find that the chemical structure of a DMFO and the binding mode of its difluoroacetylhydrazide derivative are crucial in determining the predominant hydrolysis mechanism. Our findings provide additional insights into two different mechanisms of DFMO hydrolysis, thus contributing to a better understanding of the HDAC6 inhibition by oxadiazoles in disease modulation and therapeutic intervention.
Assuntos
Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Oxidiazóis , Oxidiazóis/química , Oxidiazóis/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Desacetilase 6 de Histona/química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Cristalografia por Raios X , Cinética , Ligação Proteica , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Novel reproducible preparations of gold nanoparticles capped by aminoalcohols have been set up by reduction of HAuCl4 with NaBH4 in aqueous solution. The characterization of Au@aminoalcohol nanoparticles performed by 1H NMR, ATR-FTIR, UV-vis spectroscopies, and TEM microscopy highlighted the binding site and the nature of the Au-NH bond.
